Molecular Mechanisms of the Gut-Liver-Placenta Axis in Intrahepatic Cholestasis of Pregnancy: Microbiota-Associated Pathogenesis and Next-Generation Therapeutic Strategies.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by elevated maternal bile acid concentrations and an increased risk of adverse perinatal outcomes. Genetic susceptibility, hormonal changes, and impaired bile acid transport contribute to its development but do not fully explain the variability in disease severity and fetal outcomes. Increasing evidence suggests that gut microbiota dysbiosis and altered bile acid metabolism are associated with ICP and may participate in disease development through the gut-liver-placenta axis. In this review, we integrate evidence on bile acid-microbiota interactions during pregnancy, ICP-associated microbial and metabolic alterations, and their possible links to placental and fetal outcomes. Human studies primarily support associations among microbial alterations, bile acid profiles, and disease severity, whereas the microbiota-mediated effects on placental function and fetal injury proposed to date are supported largely by experimental models. We further discuss potential links among gut microbial dysfunction, placental oxidative stress, fetal cardiac injury, neurodevelopmental risk, offspring metabolic susceptibility, and iatrogenic prematurity. Although ursodeoxycholic acid (UDCA) improves maternal pruritus and selected biochemical indices, its effect on major perinatal outcomes remains uncertain. Ileal bile acid transporter (IBAT) inhibitors and microbiota-targeted interventions remain investigational, with insufficient pregnancy-specific evidence regarding their efficacy and maternal-fetal safety. Future studies should clarify the associated causal mechanisms and integrate metagenomic, metabolomic, and placental data to identify clinically relevant biomarkers and therapeutic targets.